Fight Aging!

Well, another year passes and here we are again, one step closer to the defeat of aging and age-related disease. Ours is an era of revolutionary progress in biotechnology, and it is starting to show. The past year was characterized by both significant fundraising and significant progress towards the clinical translation of the first complete SENS rejuvenation therapy: clearance of senescent cells from aged tissue. This is hopefully the first of numerous other SENS therapies based on repair of molecular damage to arrive over the next few years. I recently updated my predictions for the near future, looking over the parts of the field that are very close to the making the leap into for-profit startups. These are exciting times.

Regarding senescent cell clearance, I have to open by talking about fundraising. The two topics go hand in hand. Oisin Biotechnologies is the senescent cell clearance company closest to our community of supporters, seed funded back at the end of 2014 by the Methuselah Foundation and SENS Research Foundation, and led by one of the earliest donors to the Methuselah Foundation, someone who has been involved in this community for longer than I have. I've been talking about the need to extend our support for research beyond the laboratory and into startup companies, and in the tradition of doing rather than just talking about doing I participated in one of the funding rounds for Oisin Biotechnologies this year, joined by a number of other supporters. The money is going to good use, but that wasn't the big news in senescent cell clearance funding for 2016, of course. The big news was that UNITY Biotechnology landed one of the largest biotechnology industry funding rounds of recent years: $116 million in order to bring senolytic drugs to the clinic. That and the efforts that led to it will shape this field for years to come.

Over the course of the year, more evidence for the effectiveness of senescent cell clearance rolled in. Teams associated with UNITY Biotechnology showed 25% life extension in normal mice resulting from removal of senescent cells. Other work has shown restoration of function in aged lung tissue, and improved vascular health. New evidence reinforces a role of senescent cells in osteoarthritis, as well as in atherosclerosis, immunosenescence, and diabetic retinopathy. Many other papers have emerged in which researchers link senescent cells in some way to their particular areas of interest in aging. It is safe to say that the broader research community has been well and truly woken up on this topic, and are now engaged in producing a great weight of specific evidence in support of senolytic therapies as a way to delay and reverse numerous processes contributing to age-related disease. The tipping point has passed and things are moving very rapidly now in comparison to past years. How soon before the first senolytic therapies become available via medical tourism, immediately following the first human trials? Not more than a few years, I'd say. A lot of people are running, not walking, to enter this area of development at the moment.

When it comes to fundraising for SENS rejuvenation research, well, there has been a lot of that this year as well. In fact I think the long-standing grassroots of our community is reaching the point of exhaustion on this front. There is only so much water in the well when it comes to charitable support from a single community - and we've certainly given a great deal to the cause. Our community must grow to match the opportunity, but given what is happening for senescent cell clearance, I think this is a very real possibility. In crowdfunding initiatives this year, the Major Mouse Testing Program raised $50,000 for a senescent cell clearance study, and that happened back to back with the SENS Research Foundation raising $70,000 for work on one component of a universal cancer therapy based on blocking telomere lengthening. While that fundraiser was still running, Michael Greve of the Forever Healthy Foundation stepped up to pledge $10 million to SENS research and funding for the startup companies that will emerge from that research. This is the founding donation for the new SENS Project|21 initiative, seeking $50 million to bring significant segments of the SENS portfolio of rejuvenation therapies into readiness for the clinic by 2021. Somehow, in the midst of all of that excitement, the SENS Research Foundation staff found time to once again run the acclaimed Rejuvenation Biotechnology conference in August, bringing together industry and academia to build the necessary bridges for tomorrow's rejuvenation therapies.

Along the way, Ichor Therapeutics raised a funding round to build a therapy from the LysoSENS work of past years: bacterial enzymes turned into drugs to break down specific forms of harmful metabolic waste that contribute to age-related disease. BioViva recieved support from Deep Knowledge Ventures and allied with Sierra Sciences to set up a clinic in their gene therapy efforts. Ambrosia pulled in funds to run a trial of the transfer of young blood plasma to old individuals. The Methuselah Foundation launched their $500,000 research prize for tissue engineering in collaboration with NASA. Further, the founders of CellAge, one of the newer groups to enter the senescent cell clearance space, are currently running a crowdfunding initiative in order to produce better cellular senescence assay and identification technology for the research community.

Last but far from least, the end of year fundraiser for the SENS Research Foundation is coming to a close as I write as well: there is still money left in the various matching funds supplied by Michael Greve, Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! This year, we decided to match a year of donations for anyone who signs up as a SENS Patron by pledging monthly donations. This is thinking in the long term, helping to build a steady flow of donations to SENS rejuvenation research, and you'll see more of this initiative in the year ahead.

While the two topics above generate the greatest excitement and attention, there was - of course - way more to the past twelve months in longevity science than senescent cells and fundraising. Gene therapies, for example, are rapidly coming closer to reality, and the first will be available via medical tourism soon enough. Reliable and comprehensive cell coverage remains an important hurdle, though there are promising signs of progress there. The BioViva human study of one reported results for the telomerase gene therapy and, later, the follistatin gene therapy. The only thing stopping you or I from undergoing those same therapies is a matter of knowing who to call and having the necessary funds, but costs will fall rapidly in the years ahead as the number of potential providers rises and data emerges. I'm very enthusiastic about myostatin and follistatin gene therapies, and less so when it comes to telomerase gene therapy. There, I'd like to see results in species other than mice, as their telomere dynamics are significantly different. Many people inside and outside the scientific community are pushing for the development of telomerase therapies to slow aging, however, and at the present adventurous pace we'll see more human data before data in other mammals.

2016 was a big year for the cryonics community, with a great deal of attention from the media, much of surprisingly good, including profiles of supporters and the Russian KrioRus group. Cryonics simply makes sense, and we can hope that more press attention translates into a larger community of supporters making material contributions to the end goal. On that topic, I finally stopped procrastinating and signed up. As it turns out, having a backup plan only works if you actually use it. There are other signs of growth, such as the CryoSuisse initiative, and continued efforts to produce reversible vitrification for the organ transplantation industry. The Brain Preservation Foundation's technology prize was won by a cryonics approach, though not the one currently in widespread use for reasons that have a lot to do with differences in end goal between various interested factions: restoration versus copying and uploading.

Work on the SENS strategy of cross-link breaking is also forging ahead. I wrote up a state of research article early in 2016, and it remains broadly correct for the end of 2016. This research is largely funded by the SENS Research Foundation, and has yet to spread all that far beyond this small number of research groups. In effect it is in much the same position as senescent cell research found itself prior to 2011, looking for the first drug candidate and the first impressive demonstration to gain more interest from outside sources. Fortunately, in this case there is a greater flow of philanthropic funding, so we should see that breakthrough arrive within the next few years. Meanwhile, evidence continues to accumulate for the role played by cross-links in degenerative aging beyond the obvious candidates, including blood vessel stiffening, such as impaired muscle regeneration

On the mitochondrial contribution to aging, this year the SENS Research Foundation in-house team achieved allotopic expression of mitochondrial genes ATP6 and ATP8 - a big advance. The newly public company Gensight Biologics was funded with tens of millions of dollars in venture capital on the basis of doing the same for just one gene, ND4. That work too was supported by the SENS Research Foundation in its earliest stages nearly a decade ago. This is a valuable technology. Now three of thirteen mitochondrial genes can be moved to the cell nucleus: only ten to go in order to remove the contribution of mitochondrial damage to aging. Also of note is research that demonstrates a link between mitochondrial DNA deletions and the progression of sarcopenia, age-related loss of muscle mass and strength - but I am glossing over a good dozen very interesting papers on mitochondrial aging from the past twelve months in order to point out that one.

A number of relevant new organizations have arrived on the scene in 2016. Beyond UNITY Biotechnology and CellAge, mentioned above, the Global Healthspan Policy Institute, focused on lobbying, launched early in the year. On the subject of lobbying, the considerable grassroots efforts among researchers to have aging formally defined as a disease continue, alongside similar efforts to put more of an emphasis on the treatment of aging in definitions provided by influential standards bodies. Separately, the Life Extension Advocacy Foundation continues to expand their footprint in the community. There is a lot of new material at their site; worth a look.

Mitochondrially targeted antioxidants as a means to address inflammatory conditions, and maybe modestly slow the progression of aging or specific age-related conditions, have been in the news. The development of the SkQ series of compounds started in Russia, where it is already used in treatments for inflammatory eye conditions, and has now made its way into European clinical development at MitoTech. There are other lines of mitochondrial antioxidant, such as SS-31, but these are not as far along towards the clinic.

The public view of longevity assurance therapies might be coming around to support for the topic, per a survey conducted this year, provided that such therapies produce extended healthy life rather than extended frailty. In the field, it seems there is a still a considerable need for education, however. People tend to exhibit many incoherent and inconsistent positions when it comes to death, aging, and doing something about both of those topics. The comment sections of social news sites are still filled with people decrying longevity science when news comes to their attention. It is still overall a challenge to raise funds, despite our gains in recent years, and despite the growing interest on the part of various deep pockets. I have to think that the people who claim to want to age and die are failing to think critically about their own personal futures.

In Alzheimer's research, a trial of amyloid clearance via immunotherapy in humans finally worked. The field is littered with failures from the past decade, so this is a big deal. Further, there has been progress towards therapies to clear tau protein from the brain as well, including results from an an initial human trial for safety of a potential immunotherapy. On a different topic, an intriguing study appears to show that memories lost to Alzheimer's pathology can be restored via dendrite regrowth, at last in the early stages. A number of other possibilities beyond immunotherapy have emerged to reduce amyloid levels, such as drawing it out from the brain by clearing it elsewhere, or revisiting the possibility of β-secretase inhibitors. Further, the idea that amyloid builds up because physical drainage channels atrophy will get a test soon, via Methuselah Foundation funding of Leucadia Therapeutics. There are many other types of amyloid in aged tissue, however, and all those will need clearance as well. We might watch Pentraxin Therapeutics as one example of progress in this area. Like so much of this work, it proceeds at a crawl, even following a successful trial back in 2015.

Research on regeneration of an aged thymus, thereby restoring some of the decline in the immune system, continues to move forward. A recent study provided confirmation of benefits resulting from transplantation of a young thymus into an old mouse, for example. In addition to ongoing work on FOXN1 signaling as a possible way to regrow thymus tissue, it was discovered that FGF21 may also be a relevant target. Another team demonstrated that thymic decline correlates with lifespan in dog breeds. Meanwhile, tissue engineers continue to work on the production of working thymus tissue and cell therapies, aiming for the same goal of restoration.

DNA methylation patterns are a promising basis for a biomarker of aging, a test that could be used before and after a putative rejuvenation therapy to evaluate its likely long-term performance. The use of DNA methylation patterns is spreading, and evidence for their potential utility accumulates. Researchers have examined changes early in aging, assessed aging in skin tissue, determined that stroke patients are biologically older than their peers, found that people measured as being biologically older have a greater risk of cancer, and showed that known statistical differences between the life expectancies of various communities also show up in DNA methylation.

Immune system clearance and recreation has tremendous potential as therapy for autoimmunity and many aspects of age-related immunosenescence. This year, researchers demonstrated the ability to cure multiple sclerosis via a fairly simple process of destroying mature immune cells, with no need to attack blood stem cells. This is very promising for the near term development of similar therapies. All that is needed is a less harmful method of targeted cell killing, one that can be safely used by older patients. Fortunately there has been some progress in that direction in the past year, and I think we'll see more in the years ahead. Many methods currently under development in the cancer research community might be converted to this use.

Lastly for this year, a number of short essays fell from the pen to the page. Some might even be worth reading again as we look forward to 2017 and further, faster progress towards therapies to treat the causes of aging:

• Do Current Stem Cell Therapies Produce Rejuvenation?
• It is Quite Possible to Create a Senescent Cell Clearance Therapy that is Too Good
• Overfund the Life Insurance Policy that Pays for Your Cryopreservation
• The SENS Rejuvenation Biotechnology Companies
• Developing the Art of Group Buy Medical Tourism: 100 People Traveling to Pay $10-20,000 for a Rejuvenation Therapy
• Thinking About the Pipeline: Getting Therapies into Clinics
• Why Do So Few Wealthy, Sick Individuals Fund Medical Research to Treat Their Conditions?
• If I Were Going to Raise a Venture Fund, I'd Earmark 10% of Capital for Creating Startups By Funding Research that is Close to Completion
• A Short List of Potential Target Genes for Near-Future Gene Therapies Aimed at Slowing Aging or Compensating for Age-Related Damage and Decline
• Effective Therapies to Extend Healthy Life May Well be Widely Available for a Decade or More in Advance of Definitive Proof
• The Next Five Years will be a Critical Time for the Development of Rejuvenation Biotechnology after the SENS Model of Damage Repair
• On the Topic of Senescent Cells: Should We All be Trying to Take Navitoclax?
• How to Go About Using Myostatin Antibodies to Grow Muscle Today
• Request for Startups in the Rejuvenation Biotechnology Space, 2017 Edition
• The Slow Death of the Self that is Produced by the Normal Operation of Human Memory